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DRUGS USED IN CONGESTIVE HEART FAILURE 医学院药理学研究所 丁 华

DRUGS USED IN CONGESTIVE HEART FAILURE 医学院药理学研究所 丁 华. CHAPTER 27. Congestive heart failure (CHF) : the definition of CHF Essence: Cardiomyopathy of overload.

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DRUGS USED IN CONGESTIVE HEART FAILURE 医学院药理学研究所 丁 华

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  1. DRUGS USED IN CONGESTIVE HEART FAILURE医学院药理学研究所 丁 华 CHAPTER 27

  2. Congestive heart failure (CHF) : the definition of CHF Essence: Cardiomyopathy of overload

  3. Section 1 Pathophysiology of Heart Failure and The Treatment Drugs

  4. Pathophysiology of Heart Failure A. Change of cardiac function and configuration B. Change of neuroendocrine system NA、RAAS、AVP、ET、TNFα↑ ANP、NO、PGI2↓C. Change of signal transmit of β-R

  5. 心功障碍 （收缩功能↓①，舒张功能↓⑧ ） 输出量↓ 血管收缩 神经激素↑ 心肌β1R↓⑦ （RAS↑④、CA↑） 阻抗↑ 水钠潴留 ⑤ 心缩力↓ 后负荷↑② 顺应性↓ 血容量↑ 血管肥厚、重构⑥ 心肌肥大、重构⑥ 静脉淤血 前负荷↑③ 心功障碍的病理生理学与药物作用的环节

  6. CHF治疗的演变 • 20世纪20年代洋地黄开始应用 （一）纠正血流动力学异常（20世纪 50～80年代） • 1948～1968 强心苷、利尿药 • 1969～1978 血管扩张药 • 1978～1988 新型正性肌力药

  7. （二）修复衰竭心肌的生物学性质 （90年代～2001年） 90年代以来ACEI、β受体阻断药(三）逆转心肌异常（2001年起）1．扩大、强化对心衰时激活的神经 激素-细胞因子的抑制: ET、AVP、TNFα 2．基因治疗

  8. 药物治疗CHF的目的 • 1．改善血流动力学状况并尽快缓解 　　　症状。 • 2．防止心肌继续损害并延缓自然病 　　　程。 • 3．降低病死率，延长存活期。 

  9. Rationale for pharmacologic intervention in CHF The goals in treating heart failure are to improve the patient's quality of life and to prolong it. Improving hemodynamics with inotropic drugs does not decrease mortality; long-term treatment directed towards neurohormonal factors with ACE inhibitors and beta-blockers can decrease mortality

  10. Section 2 Cardiac Glycosides Digoxin（地高辛） Digitoxin（洋地黄毒苷） Cedilanide（毛花苷丙, 西地兰） Strophanthin K（毒毛花苷 k) Digitalis

  11. A. Effect on cardiac1. Positive inotropic action (1) ↑ both the force and the velocity of myocardial contraction, prolong diastolic. (2) ↑ the cardiac output. (3) ↓ myocardial oxygen consumption Pharmacological actions:

  12. Mechanism: Cardiac glycosides ↓Na+－K+ATPase [Na+] i↑ Na+/Ca2+ exchange [Ca2+] i↑ myocardial contraction ↑

  13. 2. Negative chronotropic action a. ↑vagal stimulation b. Resume sensitivity of carotid sinus baroreceptor. c.↑sensitivity of cardiac muscle to Ach.

  14. 3. Electrophysiological effect ↓AV conduction shorten ERP of atria ↑P-f automaticity， shorten ERP

  15. 强心苷对心肌电生理的作用电生理特性 窦房结 心房 房室结 浦肯野纤维自律性 降低 增高传导性 减慢有效不应期 缩短 缩短

  16. B.Effect on nerve-incretion: 1. ↓ sympathetic activity 2. ↑ pneumogastric (vagal) activity 3. ↓ renin secretion, ↓RAS 4. ↑ ANP secretion

  17. C. Diuresis effect 1.↑CO renal blood flow↑ 2.↓Na+-K+-ATPase ↓Na+ reabasorption in the tubules ↓ H2O and Na+ retention.

  18. drugs absorp% t1/2 H-E cir % last digitoxin 90~100 5d 27 2~3 w digoxin 60~ 85 36h 7 5~7dstroph K 2~5 19h 0 1~3d Pharmacokinetics

  19. 1. CHF Digoxin: 0.125～0.25mg/d，6～7d get to Css 2. Certain types of arrhythmia(1) Atrial fibrillation , atrial flutter (2) Paroxysmal supraventracular tachycardia Clinical uses

  20. 临床评价： 1997年DIG 试验(Digitalis Investigation Group trial） 6800例, 应用地高辛0.25mg/d，治疗 28～58个月。随访3.5年。 地高辛能改善症状，降低再入院率，减少 CHF恶化所致的病死率与住院率，但对总病 死率(34.8% : 35.1%)无影响。

  21. Toxicity, Prevention and Management

  22. toxicity 1. Gastrointestinal reactions Nausea and vomiting 2. CNS disturbance Changes in color vision 3. Cardiac toxicity ventricular premature contraction ventricular tachycardia ventricular fibrillation sinus bradycardia atria-ventricular block

  23. Treatment of digitalis toxicity • 1) Stop using cardiac glycosides and K+-depleting diuretics. • 2) Antiarrhythmic • KCL is administered orally or by slow, careful intravenous infusion if hypokalemia is present; • Phenytoin can be given for ventricular and atrial arrhythmia. • Lidocaine can be used to treat ventricular tachyarrhymias. • Atropine can be used to treat A-V block. • 3) Digoxin antibodies

  24. Section 3ACEI and AT1-R Antagonist • ACEI (angiotensin-converting enzyme inhibitor)： • Captopril (卡托普利) • Enalapril (依那普利) • Ramipril (雷米普利）

  25. Pharmacological action 1.Influence nerve-incretion: (1) Ang II ↓(2) Inhibit bradykinin degradation → ↑bradykinin levels →NO,EDHF, PGI2↑ (3) ↓ ALDsecretion

  26. 2. Improve hemodynamics a.Dilate blood vessels , ↓ peripheral resistance; b. Dilate coronary, improve cardiac function c.↑renal blood flow

  27. 3. Inhibit remodeling of cardiac muscle and vessel • ↓AngⅡand ALD formation , Inhibite proliferation and hypertrophy of myocardial cells and VSMC, improve cardiovascular function.

  28. Clinical Uses • 1.CHF • 2.Hypertension

  29. 临床评价: 39项8308例随机时照临床试验评价: ACEI使CHF总死亡率降低24%，显著改 善心梗后CHF患者预后，缓解临床症状， 提高运动耐力，改善生活质量，防止和 逆转心肌肥厚。ACEI可作为各型CHF的首选药，常 与利尿药，地高辛合用。

  30. ACE inhibitors are now considered to be a cornerstone in the management of most forms of heart failure and many forms of cardiac hypertrophy Braunwald &Bristow Circulation 2000

  31. Untoward Reaction • hypotension, dry cough , angioedema, hyperkalemia Contraindication: Pregnant woman Renal artery stenosis

  32. Angiotensin II receptor antagonist Losartan（氯沙坦） Valsartan（缬沙坦） Irbesartan（伊白沙坦）

  33. Characteristics: Arrest Ang II combine with AT1R (1) More selective blockers of Ang II than ACEI (2) No effect on bradykinin metabolism

  34. ARB 完全阻滞ACE和非ACE途径生成的AngII与受体结合 只阻滞AT1受体效应 不影响AT2、 AT3、 AT4受体 不影响缓激肽系统 不发生咳嗽 无AngII、Ald逃逸 ACEI 只阻滞ACE途径生成的AngII 抑制AT1、AT2、 AT3、 AT4受体效应 加强缓激肽系统作用 咳嗽相对常见 有AngII、Ald逃逸 ACEI与ARB特点比较

  35. Section 4 β-receptor blockers (adrenergic antagonists): 1. The mechanism of action in treatment of CHF • (1) Anti-sympathetic activity • a. Up-regulate β1-R in failing heart, can restore catecholamine responsiveness. • b. inhibit RAAS →↓cardiac load • c.↓myocardial damage from CA, reduce HR and myocardial oxygen consumption • (2) Anti-arrhythmia and anti-myocardial ischemia • (3)Antioxidation —carvedilol

  36. 适应症： 所有NYHA心功能Ⅱ、Ⅲ级病情稳定，LVEF<40%者，应尽早使用，平均奏效期3个月。20多个随机对照试验,>10000例NYHA心功能Ⅱ、Ⅲ级患者，长期应用β阻断剂治疗，死亡率降低34%。

  37. 美托洛尔 提高扩张型心肌病的左心室射血分数 40 35 30 25 20 标准治疗 美托洛尔 *** # 左心室 射血分数 (％) * * P<0.05 *** P<0.0001 # P=0.013 ，与标准治疗比较 基线 第一天 第一月 第三月

  38. Application attention: 1. 选择合适的制剂Selective β1-R blocker : Metoprolol、Bisoprolol (美多洛尔）(比索洛尔) Nonselective β and α1-R blocker: Carvedilol (卡维地洛）

  39. 2、应用恰当的剂量 起始量必须极小。Metoprolol 12.5mg/d Bisoprolol 1.25mg/dCarvedilol 3.125mg/d 每2～4周剂量加倍，达最大耐受 量或目标剂量后长期维持。

  40. 3、合用利尿药、ACEI、地高辛。4、密切观察可能出现的不良反应： 血流动力学恶化，心动过缓，低血 压。5、禁忌症： 支气管哮喘、心动过缓（心率< 60次/分）、Ⅱ度以上房室传导阻滞、 低血压。

  41. Section 5 Diuretics Mechanism: • decreased salt & water retention (blood volume) leads to decreased ventricular preload Clinical Effect: • decreased symptoms of heart failure (ie. edema) • decreased cardiac size leads to improved cardiac function Administration: • start with a thazide diuretic and switch to a more powerful agent as required (furosemide) • check serum electrolytes to prevent K+ loss

  42. Aldosterone antagonists Spironolacton(螺内酯) Actions: Competitive inhibition of the aldosterone receptor. ↓ H2O and Na+retention , ↓hypertrophy of myocardial cells and myocardial remodeling ↓arrhythmias and sudden death.

  43. Section 6 Vasodilators Nitrate esters(硝酸酯类) Hydralazine（肼屈嗪） Sodium nitroprusside（硝普钠) Prazosin (哌唑嗪)

  44. Mechanism of Action 1. Dilate vein ↓preload ↓ lung congestive 2. Dilate artery ↓ afterload ↑cardiac output Defects : Sympathetic and RAAS activity ↑, H2O and Na+ retention .

  45. 常用扩血管药及特点 药物 作用部位 动脉 静脉 硝酸酯类 + +++肼屈嗪 +++ -硝普钠 +++ +++哌唑嗪 ++ ++

  46. Section 7 Others • β-Adrenoceptor Agonist Dobutamine(多巴酚丁胺） Ibopamine(异波帕胺） • Phosphodiesterase Inhibitors Amrinone （氨力农） Milrinone （米力农） Vesnarinone (维司力农）

  47. Mechanism of action: β-sti PDEI (+) (-) AC PDE ATP cAMP↑ 5’-AMP

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